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Elife. 2018 Jul 30;7. pii: e37184. doi: 10.7554/eLife.37184.

An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer.

Li J#1,2,3, Choi PS#1,2,3, Chaffer CL4,5, Labella K1,2, Hwang JH1,2,3, Giacomelli AO1,2,3, Kim JW1,2,3, Ilic N1,2,3, Doench JG3, Ly SH1,2,3, Dai C1,2,3, Hagel K1,2, Hong AL1,2,3, Gjoerup O1,2,3, Goel S2,6, Ge JY1,2,7, Root DE3, Zhao JJ2,6, Brooks AN8, Weinberg RA4, Hahn WC1,2,3.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
2
Harvard Medical School, Boston, United States.
3
Broad Institute of MIT and Harvard, Cambridge, United States.
4
Whitehead Institute for Biomedical Research and MIT, Cambridge, United States.
5
Garvan Institute of Medical Research, Sydney, Australia.
6
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
7
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States.
8
University of California, Santa Cruz, Santa Cruz, United States.
#
Contributed equally

Abstract

Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT. Specifically, the skipping of FLNB exon 30 induced EMT by releasing the FOXC1 transcription factor. Moreover, skipping of FLNB exon 30 is strongly associated with EMT gene signatures in basal-like breast cancer patient samples. These observations identify a specific dysregulation of splicing, which regulates tumor cell plasticity and is frequently observed in human cancer.

KEYWORDS:

EMT; FLNB; QKI; RBFOX1; alternative splicing; basal-like breast cancer; cancer biology; cell biology; human; mouse

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